R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements

Aberrant repair of DNA double-strand breaks can recombine distant chromosomal breakpoints. Chromosomal rearrangements compromise genome function and are a hallmark of ageing. Rearrangements are challenging to detect in non-dividing cell populations, because they reflect individually rare, heterogene...

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Bibliographic Details
Published in:PLoS genetics 2021-08, Vol.17 (8), p.e1009784-e1009784
Main Authors: Ellis, David A, Reyes-Martín, Félix, Rodríguez-López, María, Cotobal, Cristina, Sun, Xi-Ming, Saintain, Quentin, Jeffares, Daniel C, Marguerat, Samuel, Tallada, Víctor A, Bähler, Jürg
Format: Article
Language:English
Subjects:
Age
Aging
Aging - genetics
Biology and Life Sciences
Brain
Breakpoints
Chromatin
Chromosome Aberrations
Chromosome Breakpoints
Chromosome rearrangements
Chromosomes
DNA Breaks, Double-Stranded
DNA damage
DNA repair
Gene Rearrangement - genetics
Gene regulation
Genetic aspects
Genetic diversity
Genetic regulation
Genetic research
Genomes
Genomic instability
Genomic Instability - genetics
Genomics - methods
Histone deacetylase
Hot spots
Microbiological research
Mitochondrial DNA
Models, Genetic
Mutation - genetics
Nucleotide sequence
Physiological aspects
Physiology
R-Loop Structures - genetics
R-loops
Regulatory proteins
Research and Analysis Methods
RNA-binding protein
Schizosaccharomyces - genetics
Schizosaccharomyces - metabolism
Schizosaccharomyces pombe Proteins - genetics
Schizosaccharomyces pombe Proteins - metabolism
Signatures
Telomere - genetics
Transcription
Transcription factors
Yeast
Yeast fungi
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Summary:Aberrant repair of DNA double-strand breaks can recombine distant chromosomal breakpoints. Chromosomal rearrangements compromise genome function and are a hallmark of ageing. Rearrangements are challenging to detect in non-dividing cell populations, because they reflect individually rare, heterogeneous events. The genomic distribution of de novo rearrangements in non-dividing cells, and their dynamics during ageing, remain therefore poorly characterized. Studies of genomic instability during ageing have focussed on mitochondrial DNA, small genetic variants, or proliferating cells. To characterize genome rearrangements during cellular ageing in non-dividing cells, we interrogated a single diagnostic measure, DNA breakpoint junctions, using Schizosaccharomyces pombe as a model system. Aberrant DNA junctions that accumulated with age were associated with microhomology sequences and R-loops. Global hotspots for age-associated breakpoint formation were evident near telomeric genes and linked to remote breakpoints elsewhere in the genome, including the mitochondrial chromosome. Formation of breakpoint junctions at global hotspots was inhibited by the Sir2 histone deacetylase and might be triggered by an age-dependent de-repression of chromatin silencing. An unexpected mechanism of genomic instability may cause more local hotspots: age-associated reduction in an RNA-binding protein triggering R-loops at target loci. This result suggests that biological processes other than transcription or replication can drive genome rearrangements. Notably, we detected similar signatures of genome rearrangements that accumulated in old brain cells of humans. These findings provide insights into the unique patterns and possible mechanisms of genome rearrangements in non-dividing cells, which can be promoted by ageing-related changes in gene-regulatory proteins.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1009784